AbstractPurpose:The primary objective was to evaluate intracranial objective response rate (iORR) in patients receiving abemaciclib with brain or leptomeningeal metastases (LM) secondary to hormone receptor–positive (HR+) metastatic breast cancer (MBC). Secondary objectives evaluated extracranial response, abemaciclib pharmacokinetics, brain metastases tissue exposure, and safety.Patients and Methods:This nonrandomized, phase II study (NCT02308020) enrolled patients in tumor subtype–specific cohorts A–D: A (HR+, HER2− MBC), B (HR+, HER2+ MBC), C (HR+ MBC LM), and D (brain metastases surgical resection). Abemaciclib 200 mg was administered twice daily as monotherapy or with endocrine therapy, or 150 mg twice daily with trastuzumab. Cohorts A and B used a Simon two-stage design.Results:In cohort A (n = 58), 3 patients were confirmed responders resulting in an iORR of 5.2% [95% confidence interval (CI), 0.0–10.9], and the intracranial clinical benefit rate (iCBR) was 24% (95% CI, 13.1–35.2). Median overall survival (OS) was 12.5 months (95% CI, 9.3–16.4). A volumetric decrease in target intracranial lesions was experienced by 38% of patients. In cohort B (n = 27), there were no confirmed intracranial responses. An iCBR of 11% (95% CI, 0.0–23.0) was observed. Median OS was 10.1 months (95% CI, 4.2–14.3). A volumetric decrease in target intracranial lesions was experienced by 22% of patients. In cohort C (n = 10), one confirmed complete parenchymal response was observed. In cohort D (n = 9), unbound brain metastases concentrations of total active abemaciclib analytes were 96- [cyclin-dependent kinase 4 (CDK4)] and 19-fold (CDK6) above in vitro IC50. Safety was consistent with prior studies.Conclusions:This study did not meet its primary endpoint. Abemaciclib was associated with an iCBR of 24% in patients with heavily pretreated HR+, HER2− MBC. Abemaciclib achieved therapeutic concentrations in brain metastases tissue, far exceeding those necessary for CDK4 and CDK6 inhibition. Further studies are warranted, including assessing novel abemaciclib-based combinations.